Inflammatory bowel disorders (IBD) encompass a spectrum of overlapping clinical diseases that appear to lack a common etiology. IBD, however, are characterized by chronic inflammation at various sites in the gastrointestinal (GI) tract. Illustrative IBD are regional enteritis (or Crohn's disease), idiopathic ulcerative colitis and infectious colitis. Most hypotheses regarding the pathogenesis of IBD concern the implication of immunologic, infectious and dietary factors.
Short chain fatty acids (SCFA) are normal components of colonic fluid. SCFA are the metabolic end product of anaerobic bacterial fermentation of carbohydrates.
Absorption of SCFA in the colon aids salt and water absorption, maintains a neutral-to-alkaline pH in the colonic lumen and prevents diarrhea which would otherwise occur if unaltered carbohydrates remain in the colon where they would act as an osmotic cathartic. SCFA absorbed from the fecal stream provide up to 85% of the energy metabolism for the cells of the distal colon and about 60% for those of the proximal colon.
The concentration of SCFA in the colonic fluid of patients with severe colitis is lower than in normal patients, and the level of SCFA in patients with severe ulcerative colitis is lower than that in patients with Crohn's disease. Vernia et al., Gastroenterology 95:1564-1568 (1988); Vernia et al., Dig. Dis. Sci., 33:1353-1358 (1988).
Studies on isolated colonic epithelial cells obtained from patients with acute and quiescent ulcerative colitis and from normal control patients have suggested that ulcerative colitis is an energy-deficient syndrome. The oxidation of one SCFA, butyric acid, to carbon dioxide was shown to be significantly lower by cells from colitis patients than in cells from normal individuals. Roediger, Lancet (Oct. 4, 1980). This result is hypothesized to be due to the lower concentration of coenzyme A present in mucosal cells of ulcerative colitis patients.
Excessively decreased concentrations of SCFA, to almost absent levels, have been observed in another colonic condition, diversion colitis (DC), which develops in response to the surgical exclusion of a portion of the colon from the fecal stream of colonic fluid. Harig et al., N. Eng. J. Med. 320:23-28 (1989). Harig et al. reported that irrigation of the colonic mucosa of DC patients with a solution of SCFA at concentrations close to those found in normal fecal water markedly improved the inflammatory process and could reverse the inflammatory condition.
The present invention relates to the utilization of SCFA in treating inflammatory bowel disorders such as ulcerative colitis and Crohn's disease.